A miR-146a-5p/TRAF6/NF-kB p65 axis regulates pancreatic cancer chemoresistance: functional validation and clinical significance
A miR-146a-5p/TRAF6/NF-kB p65 axis regulates pancreatic cancer chemoresistance: functional validation and clinical significance
复制标题
miR-146a-5p/TRAF6/NF-kB p65 轴调节胰腺癌化疗耐药：功能验证和临床意义
DOI：
10.7150/thno.40566
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Shi, Si
中科院分区：
文献类型：
--
作者：
Meng, Qingcai;Liang, Chen;Shi, Si
背景：肿瘤中microRNA （miRNA）表达失调是改变生物过程（包括化疗耐药）的关键因素。我们的研究旨在鉴定与胰腺导管腺癌（PDAC）中吉西他滨（GEM）耐药相关的mirna，并探讨其潜在机制。方法：采用miRNA微阵列技术鉴定与GEM耐药相关的miRNA。采用实时荧光定量PCR检测配对PDAC及邻近正常组织中miR-146a-5p的表达。利用生物信息学分析、荧光素酶报告基因测定和染色质免疫沉淀测定证实肿瘤坏死因子受体相关因子6 （TRAF6）是miR-146a-5p的直接靶标，并探索miR-146a-5p潜在的转录因子结合和调控。通过体外和体内实验探讨其作用机制。结果：MiR-146a-5p在PDAC患者组织中的表达与邻近正常组织相比明显降低，MiR-146a-5p的表达与PDAC患者的预后相关。功能研究表明，miR-146a-5p通过靶向TRAF6的3′-非翻译区（3′-UTR）抑制PDAC细胞增殖，并使PDAC细胞对GEM化疗增敏。MiR-146a-5p也被观察到下调TRAF6/NF-kappa B p65/P-gp轴，其调节PDAC细胞生长和化疗耐药。结论：综上所述，结果表明miR-146a-5p/TRAF6/NF-kappa B p65轴通过调节P-gp驱动胰腺化疗耐药，提示miR-146a-5p可能被用作PDAC患者新的治疗靶点和预后标志物。
Background: Dysregulated microRNA (miRNA) expression in cancer can act as a key factor that modifies biological processes, including chemoresistance. Our study aimed to identify the miRNAs associated with gemcitabine (GEM) resistance in pancreatic ductal adenocarcinoma (PDAC) and to explore the potential mechanisms.Methods: The miRNA microarray was used to identify miRNAs associated with GEM resistance. Quantitative real-time PCR was used to examine miR-146a-5p expression in paired PDAC and adjacent normal tissues. Bioinformatics analysis, luciferase reporter assays, and chromatin immunoprecipitation assays were used to confirm tumor necrosis factor receptor-associated factor 6 (TRAF6) as a direct target of miR-146a-5p and to explore the potential transcription factor binding and regulation by miR-146a-5p. In vitro and in vivo experiments were performed to investigate the mechanisms.Results: MiR-146a-5p expression was significantly decreased in PDAC tissues compared with adjacent normal tissues, and miR-146a-5p expression correlated with prognosis in PDAC patients. Functional studies indicated that miR-146a-5p suppressed PDAC cell proliferation and sensitized PDAC cells to GEM chemotherapy by targeting the 3'-untranslated region (3'-UTR) of TRAF6. MiR-146a-5p was also observed to downregulate the TRAF6/NF-kappa B p65/P-gp axis, which regulates PDAC cell growth and chemoresistance.Conclusions: Taken together, the results indicate that the miR-146a-5p/TRAF6/NF-kappa B p65 axis drives pancreatic chemoresistance by regulating P-gp, suggesting that miR-146a-5p may be utilized as a new therapeutic target and prognostic marker in PDAC patients.